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Leveraging rare genetic etiologies to advance knowledge and treatment of neuropsychiatric disorders

Award Number: U01MH119705
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/10/2019
PERIOD OF PERFORMANCE END DATE: 03/31/2026

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Leveraging rare genetic etiologies to advance knowledge and treatment of neuropsychiatric disorders - PROJECT SUMMARY Neuropsychiatric disorders (NPD), such as schizophrenia, bipolar disorder, and autism are behaviorally-defined and etiologically-heterogeneous conditions with a wide range of severity and outcomes. For cancer and other common diseases, the study of rare genetic disorders has illuminated key pathophysiological mechanisms, resulting in significant treatment advances. We hypothesize that this strategy can be successfully applied to NPD. New genomic technologies have led to the discovery of hundreds of rare genetic NPD due to copy number (CNVs) and single gene nucleotide variants (SNVs) of large effect size. However, detailed neuropsychiatric profiles have not been established for most of these conditions, due in part to difficulty recruiting adequate cohort sizes to power statistical analyses. We will capitalize on large NPD clinical populations at Geisinger, the University of Washington, and Washington University in St. Louis to recruit individuals with rare genetic disorders for this study. We will also examine the influence of additional contributors throughout the genome to the variable expressivity of neuropsychiatric symptoms in these disorders. This study will systematically examine these aspects of rare genetic NPD through the following aims: 1) Employ a highly cost-effective, genetics-first strategy to achieve baseline characterization of a large cohort with genetic NPD etiologies. Every year, as part of psychiatric, developmental, and behavioral healthcare, valuable genotype and phenotype data are generated from individuals with rare genetic NPD. We will harmonize core assessment batteries used in clinical care to leverage this high-quality data for broad data sharing and analyses on >1,000 probands, accelerating discovery and greatly reducing the research cost of multidimensional phenotyping. 2) Describe detailed phenotypic signatures in selected rare genetic NPD, including the impact of family background on variable expressivity. We will characterize quantitative neuropsychiatric traits for selected rare genetic NPD (initially 1q21.1 and 15q13.3 CNVs and CHD8 SNVs). All three disorders have shown genome-wide significance for increased risk of neuropsychiatric phenotypes, including psychosis, mood disorders, and autism. We will assess behavioral, psychiatric, and cognitive traits in 250 probands with these rare genetic NPD and their first- degree family members to explore the impact of family background on variable expressivity of neuropsychiatric symptoms. 3) Assess the contributions of common and secondary rare genomic variants to variable expressivity in rare genetic NPD. Through two sub-aims, we will explore the impact of common (polygenic risk scores) and rare (`second hits') genomic contributors on risk or resilience for neuropsychiatric symptoms. Analyzing data collected through Aims 1 and 2, in addition to a broader exploration of genomic and electronic health record data from 250,000 individuals in Geisinger's MyCode cohort, we will demonstrate how different genomic background contributors lead to clinical heterogeneity in individuals with rare genetic NPD. These studies may eventually inform individual-level prognoses for neuropsychiatric outcomes.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2023	GEISINGER CLINIC	100 N ACADEMY AVE # MC4970	DANVILLE	PA	17822	MONTOUR	USA	Mental Health Research Grants	000	5	4/29/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	GEISINGER CLINIC	100 N ACADEMY AVE # MC4970	DANVILLE	PA	17822	MONTOUR	USA	Mental Health Research Grants	000	4	9/9/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $1,826,721 )
2023	2023	GEISINGER CLINIC	100 N ACADEMY AVE	DANVILLE	PA	17822	MONTOUR	USA	Mental Health Research Grants	000	5	3/20/2023	NON-COMPETING CONTINUATION	$1,826,721
														Subtotal = $1,826,721

Issue Date FY: 2022 ( Subtotal = $1,845,135 )
2022	2022	GEISINGER CLINIC	100 N ACADEMY AVE	DANVILLE	PA	17822	MONTOUR	USA	Mental Health Research Grants	000	4	3/28/2022	NON-COMPETING CONTINUATION	$1,845,135
														Subtotal = $1,845,135

Issue Date FY: 2021 ( Subtotal = $1,866,316 )
2021	2021	GEISINGER CLINIC	100 N ACADEMY AVE	DANVILLE	PA	17822	MONTOUR	USA	Mental Health Research Grants	000	3	5/1/2021	NON-COMPETING CONTINUATION	$1,866,316
														Subtotal = $1,866,316

Issue Date FY: 2020 ( Subtotal = $1,915,591 )
2020	2020	GEISINGER CLINIC	100 N ACADEMY AVE	DANVILLE	PA	17822	MONTOUR	USA	Mental Health Research Grants	001	2	4/27/2020	SUPPLEMENT FOR EXPANSION	$191,840
2020	2020	GEISINGER CLINIC	100 N ACADEMY AVE	DANVILLE	PA	17822	MONTOUR	USA	Mental Health Research Grants	000	2	4/7/2020	NON-COMPETING CONTINUATION	$1,723,751
2020	2020	GEISINGER CLINIC	100 N ACADEMY AVE	DANVILLE	PA	17822	MONTOUR	USA	Mental Health Research Grants	002	2	5/18/2020	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $1,915,591

Issue Date FY: 2019 ( Subtotal = $1,738,336 )
2019	2019	GEISINGER CLINIC	100 N ACADEMY AVE	DANVILLE	PA	17822	MONTOUR	USA	Mental Health Research Grants	000	1	6/6/2019	NEW	$1,738,336
														Subtotal = $1,738,336

Grand Total All Awards = $9,192,099

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Leveraging rare genetic etiologies to advance knowledge and treatment of neuropsychiatric disorders

Award Number: U01MH119705

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 06/10/2019

PERIOD OF PERFORMANCE END DATE: 03/31/2026

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